Adenosine has been proposed to play an important role in the regulation of coronary blood flow. To date, there have been very few studies which examined the relationship between adenosine and prostaglandins in the regulation of myocardial blood flow. Most studies on the contribution of adenosine or other vasoactive metabolites in the autoregulatory process have been carried out in intact animals or isolated perfused organs. The proposed research would focus on to some of the problems which cannot be solved either in isolated hearts or in situ heart and the direct demonstration of the metabolism of adenosine and prostaglandins in a simple system, one free from neural and humoral influence; namely, in freshly isolated, or cultured cardiac and vascular smooth muscle cells. In these preparations, the metabolism of adenosine will be studied under normal and hypoxic conditions, including its extracellular release at varying oxygen tensions and time. These studies together with the reported studies in literature will provide a clear understanding of the role of adenosine and prostaglandins and their relationship in the metabolic regulation of coronary blood flow. Additionally, the proposed studies on vascular smooth muscle will provide information of the metabolic mediation of blood flow with special emphasis on the role of adenosine and other vasoactive metabolites. Thus, the main objectives of this proposal are: (a) to investigate further the metabolic regulation of coronary blood flow, (b) to investigate the role of vasoactive metabolites, adenosine and prostaglandins in the hypoxic cardiac and vascular smooth muscle cells, and (c) to investigate the pathways involved in the synthesis and degradation of adenosine in cardiac and vascular smooth muscle cells and the effect of selected drugs (e.g., dipyridamole, a coronary dilator, and indomethacin, a prostaglandin synthetase inhibitor) on the metabolism of adenosine. In summary, the data derived from these studies could represent a major advance in our understanding of local coronary blood flow regulation and should provide a rational basis for the therapeutic alteration of regional blood flow in low flow states such as coronary insufficiency, myocardial infarction and shock.